Clinical and functional characterization of the Pro1198Leu ABCC8 gene mutation associated with permanent neonatal diabetes mellitus.
Clinical and functional characterization of the Pro1198Leu ABCC8 gene mutation associated with permanent neonatal diabetes mellitus.
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DOI：
10.1111/jdi.12049
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发表时间：
2013-05-06
影响因子：
3.2
通讯作者：
Akamizu T
中科院分区：
文献类型：
--
作者：
Takagi T;Furuta H;Miyawaki M;Nagashima K;Shimada T;Doi A;Matsuno S;Tanaka D;Nishi M;Sasaki H;Inagaki N;Yoshikawa N;Nanjo K;Akamizu T
三磷酸腺苷（ATP）敏感钾（KATP）通道是胰腺β细胞胰岛素分泌的关键组成部分。编码KATP通道磺酰脲受体亚基的ABCC8激活突变与新生儿糖尿病（NDM）的发展有关。目的是研究与永久性NDM （PNDM）相关的Pro1198Leu ABCC8基因突变的临床和功能特征。在1例确诊为PNDM的12岁女孩中，对KCNJ11、ABCC8和INS的编码区和保守剪接位点进行了突变筛选。在COS‐1细胞中通过膜片钳实验检测了所鉴定的突变通道的功能特性。我们还研究了两组口服磺脲类药物在体外和患者体内的疗效差异。我们发现了一个杂合错义突变（c.3593）C>T, Pro1198Leu)在ABCC8中的表达。突变残基（P1198）位于磺脲类药物（如甲磺丁酰胺或格列齐特）的推定结合位点内。在膜片钳实验中，突变型通道对ATP的敏感性低于野生型。此外，突变体通道对甲苯磺丁酰胺的敏感性也降低了。除了甲苯丁酰胺/格列齐特结合位点外，格列本脲还被认为与另一个位点结合。格列本脲在体外和患者体内均比其他磺脲类药物更有效。患者的治疗最终能够从胰岛素注射切换到口服格列本脲。我们在一名PNDM患者中发现了Pro1198Leu ABCC8突变，并阐明了其功能和临床特征。本研究结果为理解PNDM提供了新的信息。
The adenosine triphosphate (ATP)‐sensitive potassium (KATP) channel is a key component of insulin secretion in pancreatic β‐cells. Activating mutations in ABCC8 encoding for the sulfonylurea receptor subunit of the KATP channel have been associated with the development of neonatal diabetes mellitus (NDM). The aim was to investigate clinical and functional characterization of the Pro1198Leu ABCC8 gene mutation associated with permanent NDM (PNDM). The coding regions and conserved splice sites of KCNJ11,ABCC8 and INS were screened for mutations in a 12‐year‐old girl diagnosed with PNDM. The functional property of the mutant channel identified was examined with patch‐clamp experiments in COS‐1 cells. We also investigated the difference of effectiveness between two groups of oral sulfonylureas in vitro and in the patient. We identified a heterozygous missense mutation (c.3593 C>T, Pro1198Leu) in ABCC8. The mutated residue (P1198) is located within a putative binding site of sulfonylureas, such as tolbutamide or gliclazide. In patch‐clamp experiments, the mutant channel was less ATP sensitive than the wild type. Furthermore, the sensitivity to tolbutamide was also reduced in the mutant channel. In addition to the tolbutamide/gliclazide binding site, glibenclamide is thought to also bind to another site. Glibenclamide was more effective than other sulfonylureas in vitro and in the patient. The treatment of the patient was finally able to be switched from insulin injection to oral glibenclamide. We identified the Pro1198Leu ABCC8 mutation in a PNDM patient, and clarified the functional and clinical characterization. The present findings provide new information for understanding PNDM.
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作者：
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